Progress Reports

Reporting Period:

Year 1

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Genetic diseases of the blood system range from blood cancers (e.g., leukemias) to autoimmune diseases (e.g., Type 1 diabetes, multiple sclerosis and rheumatoid arthritis). As such, they are amongst the most severe diseases afflicting California and the world as a whole. These genetic blood diseases are caused when our body's own blood cells go awry.
It has been shown that many types of genetic blood disease can be treated, if not outright cured, by replacing a patient's faulty blood cells with new, healthy blood cells. Clinical trials have shown encouraging results for patients with various blood cancers and autoimmune disorders when they are injected with new, healthy blood-forming stem cells, thereby generating a new and healthy blood system and replacing their own faulty blood cells. While these results are encouraging, there is a long ways yet to go to make such treatments safer for patients and more commonplace in the clinic.
In the past funding period, we have made significant advances towards this goal of replacing patients' faulty blood systems with new, stem cell-derived blood systems. Firstly, we have made steps towards generating new human blood stem cells in a dish from embryonic stem cells. The eventual goal of this salient is to mass-producing new blood stem cells in a dish for patients with genetic blood diseases that are in need of them. Secondly, we have identified combinations of biological agents (known as antibodies) that can safely deplete mouse blood stem cells. The eventual goal of this second line of research is to eventually identify combinations of similar biological agents that can safely deplete the faulty blood stem cells in human patients with genetic blood diseases, allowing us to then inject new, healthy blood stem cells to regenerate a healthy blood system.

Reporting Period:

Year 3

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<p>Hematopoietic stem cell (HSC) transplantation (HSCT) can offer a curative treatment for a wide range of diseases including genetic blood disorders, autoimmune diseases and hematologic malignancies, and it can also induce immune-tolerance for organ or cell transplantation. However there are still significant barriers to the broad clinical application of HSCT: 1. Currently, HSCT relies on human donors, as the methods for generating mature, fully functional HSCs from human pluripotent stem cells (hPSC) in vitro are still lacking; 2. The toxicity of conditioning regimens drastically limits the patient populations that are being offered HSCT. Here, we report significant progress towards removing these barriers: 1. Based on our knowledge of the developmental biology of HSCs, we improved the protocols for generating HSC in vitro from hPSC; 2. We developed an antibody-based conditioning method to eliminate endogenous HSC so that donor HSCs can engraft into the vacated niches in the bone marrow, and to transiently suppress immune T and NK cells to prevent rejection of donor HSCs. This is a major accomplishment, as it suggests that we can safely deplete endogenous HSC and transplant donor HSC to achieve high and stable long-term engraftment and reconstitution of the blood and immune systems without chemotherapy or radiation. Using this method, we were able to transplant purified HSCs from a completely mis-matched donor. The engrafted HSC induced transplantation tolerance to organs from the same donor, but not to a genetically different donor. &nbsp;This implies that in the future, when PSC-derived HSCs are available for transplantation, fewer lines will be sufficient to offer this therapy to a wide and genetically diverse patient population. Induction of transplantation tolerance by the engrafted HSCs has far reaching implication in regenerative medicine, as it will enable co-transplantation of HSCs and any other organ or cell-based therapies from the same donor or hPSC line.</p>

A goal of stem-cell therapy is to transplant into a patient “tissue-specific” stem cells, which can regenerate a particular type of healthy tissue (e.g., heart or blood cells). A major obstacle to this goal is obtaining tissue-specific stem cells that (1) are available in sufficient numbers; and (2) will not be rejected by the recipient. One approach to these challenges is to generate tissue-specific stem cells in the lab from “pluripotent” stem cells, which can produce all types of tissue-specific stem cells. The rationale is that pluripotent stem cells that will be tolerated are easier to directly obtain than tissue-specific stem cells that will be tolerated. Furthermore, descendants of a tolerated pluripotent stem cell will also be tolerated and can be produced abundantly.

The goal of the proposed project is to develop techniques for generating transplantable blood-forming stem cells from pluripotent stem cells. In pursuit of this goal, we will study how blood-forming stem cells arise during development. We will also test new methods--less toxic than current chemotherapy and radiation--for preparing recipients for transplantation of blood-forming stem cells.

Additional benefit: Successful transplantation of blood-forming stem cells allows the recipient to tolerate other tissue or organ transplants from the same donor. Thus, transplanted blood-forming stem cells could allow people to receive organs that they may otherwise reject, without taking immune-suppressing drugs.

Statement of Benefit to California:

We aim to generate from stem cells that can produce all tissues of the body those stem cells that specifically form blood. We will also test new methods--less toxic than current chemotherapy and radiation--for pretreatment before transplantation of blood-forming stem cells. A large number of patients in California could benefit from advances in this field, primarily those with diseases affecting the production of blood and immune cells: leukemia, lymphoma, thalassemia, certain types of anemia, immune deficiency diseases, autoimmune diseases (e.g., lupus), etc. For leukemia and lymphoma alone, in 2014 in California, there will be an estimated 12,060 newly diagnosed cases, 103,400 existing cases, and 4,620 deaths (per the California Cancer Registry). The cost of these blood cancers are difficult to estimate but they account for 6% of cancers in women and 9% in men in California, where the estimated cost of cancer per year is $28.3 billion.

The reagents generated in these studies can be patented, forming an intellectual property portfolio shared by the state. The funds generated from the licensing of these technologies will provide revenue for the state, help increase hiring of faculty and staff (many of whom will bring in other, out-of-state funds to support their research) and could reduce the costs of related clinical trials. Only California businesses are likely to be able to license these reagents and to develop them into diagnostic and therapeutic entities.